The proposed seven year program of research (Leadership and Excellence In Alzheimer's Disease) (LEAD Award) deals entirely with cellular, molecular and genetic aspects of the neurobiology of aging and Alzheimer's disease. The P.I., whose research career has been devoted to genetic approaches to the pathobiology of aging, will focus, in collaboration with two molecular geneticists (K. Fukuchi & S. Deeb), upon a search for genetic loci which can suppress neurotoxicity mediated by the beta amyloid precursor protein. A recently developed embryonal carcinoma cell culture system, in which transfected vectors can be overexpressed in differentiating neural progeny, will be used as a vehicle for the characterization of both known candidate and anonymous cDNA suppressors. Amyloidogenesis and its suppression will also be investigated using a model of inducible overexpression of endogenous wild type or mutant APP. In collaboration with the laboratory of Lee Hartwell, yeast cells will also be employed as vehicles for the detection of cDNA's coding for proteins that interact with specific domains of APP; these too would serve as candidate suppressors of beta amyloidogenesis. Finally, selected suppressors would be biologically assayed in hybrid lines of beta-amyloidogenic transgenic mice (including those developed via the embryonal stem cell route). The discovery of such suppressor loci will have two major applications: 1) as candidate loci for the linkage analysis of various forms of familial AD, the major theme of our ADRC; 2) as a basis for the design of novel preventative and therapeutic agents. The proposal is also designed to nurture the careers of four Assistant Professors. Dr. Margaret Miller (Psychiatry) will be supported for seven years to permit her to extend her investigations of the effects of sex steroid hormones upon the central nervous system of rats, basic research of great potential relevance to patterns of neurobiological aging among millions of American women receiving such exogenous steroids. Pilot studies are proposed by Dr. Glenna Burmer (Pathology) for a method to determine the phase relationships of genetic markers, research that could lead to a major enhancement in the efficiency of linkage analysis in AD and other disorders. Dr. James Thomas (Genetics) will do pilot studies on the genetic control of neuronal stability in the nematode, C. elegans. Dr. Mark Dubach (Psychiatry & Primate Center) will do preliminary tests of the hypothesis that inhibition of lysosomal proteases by leupeptin can lead to beta-amyloidogenesis and other neuropathological stigmata of AD in Macaca fascicularis.